Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with significantly increased cardiovascular (CV) morbidity and mortality. Systemic inflammation from active RA has been strongly linked to cardiovascular death and subclinical atherosclerosis in RA patients. Traditional CV risk factors contribute to CV risk in RA, but these risk factors alone are not sufficient to explain the magnitude of CV risk associated with RA. Changes in novel risk factors such as the quality as well as quantity of high density lipoprotein (HDL) may be necessary to more fully explain CV risk in RA. Substantial evidence has accumulated that dysfunctional HDL may play a role in the development of atherosclerosis. The presence of abnormal, pro-inflammatory HDL (piHDL) is associated with coronary heart disease (CHD) in the general population and is more prevalent in patients with RA. Our preliminary data in a cross-sectional RA cohort suggests a significant correlation of HDL function with RA disease activity and systemic inflammation. Higher disease activity, ESR, and C-reactive protein were associated with worse HDL function. Large, well designed prospective clinical studies are needed to further evaluate the effects of disease activity as well as disease treatments on HDL function and other biomarkers of CV risk in patients with RA. We propose: 1)To evaluate the effects of disease activity on traditional and novel biomarkers of CV risk in a 755 patient early RA cohort during two years of treatment, 2)To evaluate the effects of methotrexate monotherapy versus methotrexate combination therapies on traditional and novel biomarkers of CV risk. We hypothesize that systemic inflammation from active RA alters both the quantity and protein structure/function of HDL, impairing its capacity to prevent oxidation of LDL, thus enhancing the development of atherosclerosis. We also hypothesize that improvement in disease activity improves both traditional and novel biomarkers of CV risk, and that methotrexate combination therapy may be more effective at improving CV biomarkers by more effectively controlling disease activity. The significance of the proposed work lies in its potential to conclusively define the effects of RA disease activity, treatment, and disease improvement on both traditional and novel biomarkers of atherosclerotic risk in specimens from a large, 755 patient early RA cohort with minimal prior disease modifying anti-rheumatic drug (DMARD) therapy who were randomized to methotrexate monotherapy or methotrexate combination therapy with etanercept or hydroxychloroquine/sulfasalazine and followed for two years. Long term reduction of CV risk biomarkers with aggressive control of disease activity would provide further rationale for aggressive treatment of early RA. However, the inability to improve novel and/or traditional CV risk markers with currently available DMARDS would provide rationale for the addition of early treatment of RA patients with CV therapies such as statins and other novel CV risk reduction drugs currently in development. PUBLIC HEALTH RELEVANCE: Patients with rheumatoid arthritis (RA) die 3-18 years earlier then members of the general population and cardiovascular (CV) disease is the leading cause of death. This study will evaluate if aggressive arthritis control with current treatments can improve novel and traditional biomarkers of CV risk in early RA patients followed for two years. Improvement in CV risk markers with disease control would provide further rationale for aggressive treatment of early RA patients, while lack of improvement in CV markers would suggest the need for early treatment with CV protective therapies such as statins (cholesterol-lowering medications) and/or other novel CV risk reduction drugs currently in development.